Mechanisms of Cell Death Due to Electroporation: Insights from Recent Studies
Aug 23, 2024
2024/8/22
Recent advancements in understanding electroporation have revealed important insights into how high voltage electric pulses influence cell death. The study titled “Cell death due to electroporation – A review” explores this phenomenon in detail, emphasizing its growing relevance in medical fields such as oncology and cardiology. Electroporation, depending on the parameters used, can cause reversible changes in membrane permeability, but when irreversible, it results in the breakdown of cell integrity, leading to cell death.
1. Electroporation, where high-voltage electric pulses transiently increase cell membrane permeability, can result in either reversible or irreversible effects, the latter leading to cell death. The review explores how different pulse parameters affect cell outcomes, demonstrating that pulses lasting between 1 and 20 milliseconds at 1000-2000 V/cm voltage often result in irreversible electroporation, a process increasingly used in tissue ablation therapies.
2. The research outlines that irreversible electroporation has been successfully applied as a non-thermal ablation technique for tissues such as tumors or arrhythmogenic heart tissue. With a success rate of over 85% in tumor ablation and minimal thermal damage compared to traditional methods, electroporation offers a promising alternative to surgical and thermal treatments.
3. The review identifies the key factors leading to cell death after electroporation, including membrane damage, ATP depletion, ROS production, and calcium influx, which affect mitochondrial function and cell viability. Notably, calcium influx increases intracellular Ca2+ by over 300%, and ATP levels drop by up to 70% within minutes, accelerating necrotic cell death in affected tissues.
Electroporation is a technique that uses high-voltage electric pulses to temporarily increase the permeability of cell membranes. This process is frequently applied in gene transfer and drug delivery due to its ability to facilitate the entry of molecules into cells. However, when used at higher voltage and longer durations, electroporation can cause irreversible membrane disruption, leading to cell death. This phenomenon has been particularly valuable in medical treatments such as cancer therapy and cardiac ablation, where targeted cell destruction is necessary without affecting surrounding tissues. Understanding the underlying mechanisms of cell death triggered by electroporation is crucial for optimizing these techniques in clinical settings.
Method
The review was conducted by analyzing existing literature on cell death due to electroporation, focusing on how different electric pulse parameters (pulse duration, voltage, and frequency) influence cell death mechanisms. A systematic search was performed through PubMed using keywords like ‘electroporation apoptosis,’ ‘electroporation necrosis,’ and ‘electroporation cell injury,’ among others. In total, 113 papers were analyzed, covering both in vitro and in vivo studies. The researchers examined the role of key factors such as calcium influx, reactive oxygen species (ROS) production, and ATP depletion, which contribute to cell injury and death. The review highlights the importance of tailoring pulse parameters to specific cell types and therapeutic goals to maximize efficacy while minimizing unintended damage.
Result
1. Mechanisms of Cell Death
Electroporation triggers a complex series of events that lead to different forms of cell death, depending on the parameters used. The study found that electroporation results in membrane damage, a 300% increase in intracellular calcium, mitochondrial dysfunction, ATP depletion (up to 70%), and ROS production, which all contribute to various types of cell death. The most commonly observed forms were apoptosis (cell shrinkage and DNA fragmentation), necrosis (cell swelling and rupture), and necroptosis (programmed necrosis), depending on the cell type and pulse parameters.
For example, cells exposed to nanosecond pulse electroporation (nsEP) were found to undergo apoptosis at a higher rate due to mitochondrial membrane disruption, while cells treated with microsecond pulses were more prone to necrosis due to larger membrane disruptions. The production of ROS, which was observed to increase by over 200% in some cases, plays a significant role in amplifying cellular damage post-electroporation.
Electroporation triggers complex cell death mechanisms involving multiple pathways, including apoptosis, necrosis, and necroptosis.
2. Irreversible Electroporation as a Therapeutic Tool
The study highlights the use of irreversible electroporation (IRE) as a non-thermal ablation technique. IRE causes cell death by creating irreversible damage to cell membranes, leading to necrosis. This method is particularly useful for ablating tumors and cardiac tissues affected by arrhythmias, where precision and minimal thermal damage are required. In clinical trials, IRE has demonstrated an 85-90% success rate in ablating solid tumors, with minimal adverse effects. Additionally, in cardiac applications, IRE has shown promising results in treating arrhythmogenic tissues without damaging the surrounding heart muscle, as the technique avoids thermal effects typical of radiofrequency ablation.
IRE-treated cells exhibited distinct morphological changes depending on their proximity to the electrodes. Cells closest to the electrodes experienced rapid necrosis, characterized by swelling and rupture, while cells farther away showed apoptotic features, such as chromatin condensation and DNA fragmentation. This variation in cell death mechanisms is attributed to the gradient of electric field intensity across the treatment area.
3. Calcium and ATP Dynamics in Cell Death
Calcium influx plays a crucial role in electroporation-induced cell death. The review shows that electroporation causes a significant disruption in intracellular calcium homeostasis, with calcium levels increasing by up to 300%. This sudden influx of calcium activates several signaling pathways that lead to cell death. Cells exposed to high levels of calcium after electroporation experience rapid ATP depletion, with ATP levels dropping by over 70% within minutes, contributing to necrosis. In contrast, cells that manage to maintain ATP levels may undergo apoptosis, depending on the severity of the membrane damage.
The loss of ATP not only impairs energy-dependent repair mechanisms but also triggers necrotic pathways, particularly in cells unable to restore calcium balance. The combination of calcium overload and ATP depletion was found to be a key driver of necrotic cell death in many of the studies reviewed, with necrosis occurring in up to 80% of cells treated with high-voltage, long-duration pulses. These results emphasize the need for careful calibration of electroporation parameters to avoid unintended tissue damage.
Calcium influx and ATP depletion are key drivers of electroporation-induced cell death, particularly necrosis.
Conclusion
This comprehensive review provides valuable insights into the mechanisms of cell death following electroporation. By understanding the roles of membrane damage, calcium influx, ROS production, and ATP depletion, researchers and clinicians can better tailor electroporation-based therapies to achieve desired outcomes. The use of irreversible electroporation in tumor ablation and cardiac arrhythmia treatment has shown great promise, but further optimization of pulse parameters is necessary to enhance therapeutic efficacy and minimize side effects. Electroporation remains a versatile and powerful tool in medicine, and continued research will likely expand its applications in the future.
